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. 2003 Aug;12(4):229–235. doi: 10.1080/09629350310001599675

High serum level of endostatin in multiple myeloma at diagnosis but not in the plateau phase after treatment.

Halina Urbańska-Ryś 1, Tadeusz Robak 1
PMCID: PMC1781619  PMID: 14514474

Abstract

We investigated the serum concentration of endostatin in 84 patients with multiple myeloma (MM) and in 13 healthy controls. The level of measured anti-angiogenic agent was correlated with the phase and stage of the disease, and most importantly with clinical and laboratory parameters depicting the disease activity (haemoglobin, creatinine, albumins, calcium, M-component, C-reactive protein, beta2-microglobulin, lactate dehydrogenase, stage of bone disease) as well as serum levels of pro-angiogenic cytokines such as vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor and transforming growth factor-beta. The median serum level of endostatin in MM patients was 58 ng/ml and was statistically significantly higher than in the control group (median, 40 ng/ml; p=0.015). MM patients in phase I (at diagnosis) had higher levels of endostatin (median, 69 ng/ml) than those in phase II (plateau phase after treatment) (median, 49 pg/ml; p=0.044). We did not find any statistical correlation between the level of endostatin and stage of MM according to the Durie and Salmon system. The serum concentration of endostatin in MM patients with a normal level of albumins was significantly higher than in others with hypoalbuminaemia (median, 62 ng/ml versus 39 ng/ml; p=0.033). Also, patients with a normal value of lactate dehydrogenase had a higher concentration of endostatin than those with values >425 U/l (median, 70 ng/ml versus 39 ng/ml; p=0.019). We did not show any statistical correlation between the concentration of endostatin and level of haemoglobin, creatinine, calcium, C-reactive protein, beta2-microglobulin and stage of bone disease. We failed to find positive or negative correlations between the level of endostatin and vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor and transforming growth factor-beta. The concentration of endostatin did not influence the probability of survival in MM patients in our study. In conclusion, our data indicate that endostatin has a higher level in MM patients than in healthy controls. Highest values were stated in active phases of the disease (at presentation and in progression). Different clinical and laboratory parameters generally do not influence the concentration of endostatin (except albumins and lactate dehydrogenase).

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Selected References

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  1. Bertolini F., Fusetti L., Mancuso P., Gobbi A., Corsini C., Ferrucci P. F., Martinelli G., Pruneri G. Endostatin, an antiangiogenic drug, induces tumor stabilization after chemotherapy or anti-CD20 therapy in a NOD/SCID mouse model of human high-grade non-Hodgkin lymphoma. Blood. 2000 Jul 1;96(1):282–287. [PubMed] [Google Scholar]
  2. Dhanabal M., Ramchandran R., Waterman M. J., Lu H., Knebelmann B., Segal M., Sukhatme V. P. Endostatin induces endothelial cell apoptosis. J Biol Chem. 1999 Apr 23;274(17):11721–11726. doi: 10.1074/jbc.274.17.11721. [DOI] [PubMed] [Google Scholar]
  3. Dhanabal M., Volk R., Ramchandran R., Simons M., Sukhatme V. P. Cloning, expression, and in vitro activity of human endostatin. Biochem Biophys Res Commun. 1999 May 10;258(2):345–352. doi: 10.1006/bbrc.1999.0595. [DOI] [PubMed] [Google Scholar]
  4. Dixelius J., Larsson H., Sasaki T., Holmqvist K., Lu L., Engström A., Timpl R., Welsh M., Claesson-Welsh L. Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood. 2000 Jun 1;95(11):3403–3411. [PubMed] [Google Scholar]
  5. Durie B. G., Salmon S. E. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975 Sep;36(3):842–854. doi: 10.1002/1097-0142(197509)36:3<842::aid-cncr2820360303>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  6. Feldman A. L., Pak H., Yang J. C., Alexander H. R., Jr, Libutti S. K. Serum endostatin levels are elevated in patients with soft tissue sarcoma. Cancer. 2001 Apr 15;91(8):1525–1529. doi: 10.1002/1097-0142(20010415)91:8<1525::aid-cncr1161>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  7. Feldman A. L., Tamarkin L., Paciotti G. F., Simpson B. W., Linehan W. M., Yang J. C., Fogler W. E., Turner E. M., Alexander H. R., Jr, Libutti S. K. Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with stage IV clear cell renal cancer. Clin Cancer Res. 2000 Dec;6(12):4628–4634. [PubMed] [Google Scholar]
  8. Hanahan D., Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996 Aug 9;86(3):353–364. doi: 10.1016/s0092-8674(00)80108-7. [DOI] [PubMed] [Google Scholar]
  9. Hohenester E., Sasaki T., Olsen B. R., Timpl R. Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution. EMBO J. 1998 Mar 16;17(6):1656–1664. doi: 10.1093/emboj/17.6.1656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jin X., Bookstein R., Wills K., Avanzini J., Tsai V., LaFace D., Terracina G., Shi B., Nielsen L. L. Evaluation of endostatin antiangiogenesis gene therapy in vitro and in vivo. Cancer Gene Ther. 2001 Dec;8(12):982–989. doi: 10.1038/sj.cgt.7700396. [DOI] [PubMed] [Google Scholar]
  11. Kay N. E., Bone N. D., Tschumper R. C., Howell K. H., Geyer S. M., Dewald G. W., Hanson C. A., Jelinek D. F. B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules. Leukemia. 2002 May;16(5):911–919. doi: 10.1038/sj.leu.2402467. [DOI] [PubMed] [Google Scholar]
  12. Kerbel R. S. Tumor angiogenesis: past, present and the near future. Carcinogenesis. 2000 Mar;21(3):505–515. doi: 10.1093/carcin/21.3.505. [DOI] [PubMed] [Google Scholar]
  13. Kim Y. M., Jang J. W., Lee O. H., Yeon J., Choi E. Y., Kim K. W., Lee S. T., Kwon Y. G. Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase. Cancer Res. 2000 Oct 1;60(19):5410–5413. [PubMed] [Google Scholar]
  14. Kisker O., Becker C. M., Prox D., Fannon M., D'Amato R., Flynn E., Fogler W. E., Sim B. K., Allred E. N., Pirie-Shepherd S. R. Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model. Cancer Res. 2001 Oct 15;61(20):7669–7674. [PubMed] [Google Scholar]
  15. Lai Raymond, Estey Elihu, Shen Yu, Despa Simona, Kantarjian Hagop, Beran Miloslav, Maushouri Taghi, Quackenbuch Robert C., Keating Micheal, Albitar Maher. Clinical significance of plasma endostatin in acute myeloid leukemia/myelodysplastic syndrome. Cancer. 2002 Jan 1;94(1):14–17. doi: 10.1002/cncr.10200. [DOI] [PubMed] [Google Scholar]
  16. MacDonald N. J., Shivers W. Y., Narum D. L., Plum S. M., Wingard J. N., Fuhrmann S. R., Liang H., Holland-Linn J., Chen D. H., Sim B. K. Endostatin binds tropomyosin. A potential modulator of the antitumor activity of endostatin. J Biol Chem. 2001 May 2;276(27):25190–25196. doi: 10.1074/jbc.M100743200. [DOI] [PubMed] [Google Scholar]
  17. Mundhenke C., Thomas J. P., Wilding G., Lee F. T., Kelzc F., Chappell R., Neider R., Sebree L. A., Friedl A. Tissue examination to monitor antiangiogenic therapy: a phase I clinical trial with endostatin. Clin Cancer Res. 2001 Nov;7(11):3366–3374. [PubMed] [Google Scholar]
  18. Nagashima M., Asano G., Yoshino S. Imbalance in production between vascular endothelial growth factor and endostatin in patients with rheumatoid arthritis. J Rheumatol. 2000 Oct;27(10):2339–2342. [PubMed] [Google Scholar]
  19. O'Reilly M. S., Boehm T., Shing Y., Fukai N., Vasios G., Lane W. S., Flynn E., Birkhead J. R., Olsen B. R., Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997 Jan 24;88(2):277–285. doi: 10.1016/s0092-8674(00)81848-6. [DOI] [PubMed] [Google Scholar]
  20. Prehn R. T. The inhibition of tumor growth by tumor mass. Cancer Res. 1991 Jan 1;51(1):2–4. [PubMed] [Google Scholar]
  21. Robak E., Woźniacka A., Sysa-Jedrzejowska A., Stepień H., Robak T. Circulating angiogenesis inhibitor endostatin and positive endothelial growth regulators in patients with systemic lupus erythematosus. Lupus. 2002;11(6):348–355. doi: 10.1191/0961203302lu199oa. [DOI] [PubMed] [Google Scholar]
  22. Shichiri M., Hirata Y. Antiangiogenesis signals by endostatin. FASEB J. 2001 Apr;15(6):1044–1053. doi: 10.1096/fj.99-1083com. [DOI] [PubMed] [Google Scholar]
  23. Taddei L., Chiarugi P., Brogelli L., Cirri P., Magnelli L., Raugei G., Ziche M., Granger H. J., Chiarugi V., Ramponi G. Inhibitory effect of full-length human endostatin on in vitro angiogenesis. Biochem Biophys Res Commun. 1999 Sep 24;263(2):340–345. doi: 10.1006/bbrc.1999.1342. [DOI] [PubMed] [Google Scholar]
  24. Talks K. L., Harris A. L. Current status of antiangiogenic factors. Br J Haematol. 2000 Jun;109(3):477–489. doi: 10.1046/j.1365-2141.2000.01864.x. [DOI] [PubMed] [Google Scholar]
  25. Tosi P., Tura S. Antiangiogenic therapy in multiple myeloma. Acta Haematol. 2001;106(4):208–213. doi: 10.1159/000046617. [DOI] [PubMed] [Google Scholar]
  26. Urba ska-Rys Halina, Wierzbowska Agnieszka, Robak Tadeusz. Circulating angiogenic cytokines in multiple myeloma and related disorders. Eur Cytokine Netw. 2003 Jan-Mar;14(1):40–51. [PubMed] [Google Scholar]
  27. Urbańska-Ryś H., Wiersbowska A., Stepień H., Robak T. Relationship between circulating interleukin-10 (IL-10) with interleukin-6 (IL-6) type cytokines (IL-6, interleukin-11 (IL-11), oncostatin M (OSM)) and soluble interleukin-6 (IL-6) receptor (sIL-6R) in patients with multiple myeloma. Eur Cytokine Netw. 2000 Sep;11(3):443–451. [PubMed] [Google Scholar]
  28. Wierzbowska A., Urbańska-Ryś H., Robak T. Circulating IL-6-type cytokines and sIL-6R in patients with multiple myeloma. Br J Haematol. 1999 May;105(2):412–419. [PubMed] [Google Scholar]
  29. Wu P., Yonekura H., Li H., Nozaki I., Tomono Y., Naito I., Ninomiya Y., Yamamoto H. Hypoxia down-regulates endostatin production by human microvascular endothelial cells and pericytes. Biochem Biophys Res Commun. 2001 Nov 16;288(5):1149–1154. doi: 10.1006/bbrc.2001.5903. [DOI] [PubMed] [Google Scholar]
  30. Yamaguchi N., Anand-Apte B., Lee M., Sasaki T., Fukai N., Shapiro R., Que I., Lowik C., Timpl R., Olsen B. R. Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding. EMBO J. 1999 Aug 16;18(16):4414–4423. doi: 10.1093/emboj/18.16.4414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zorick T. S., Mustacchi Z., Bando S. Y., Zatz M., Moreira-Filho C. A., Olsen B., Passos-Bueno M. R. High serum endostatin levels in Down syndrome: implications for improved treatment and prevention of solid tumours. Eur J Hum Genet. 2001 Nov;9(11):811–814. doi: 10.1038/sj.ejhg.5200721. [DOI] [PubMed] [Google Scholar]

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